Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

McAlpine, Cameron S.; Park, Joseph; Griciuc, Ana; Kim, Eun‐Hee; Choi, Se Hoon; Iwamoto, Yoshiko; Kiss, Máté G.; Christie, Kathleen A.; Vinegoni, Claudio; Poller, Wolfram C.; Mindur, John E.; Chan, Christopher T.; He, Shasha; Janssen, Henrike; Wong, Lai Ping; Downey, Jeffrey; Singh, Sumnima; Anzai, Atsushi; Kahles, Florian; Jorfi, Mehdi; Feruglio, Paolo Fumene; Sadreyev, Ruslan I.; Weissleder, Ralph; Kleinstiver, Benjamin P.; Nahrendorf, Matthias; Tanzi, Rudolph E.; Świrski, Filip K.

doi:10.1038/s41586-021-03734-6

Cited by 215 publications

(151 citation statements)

References 39 publications

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“…In AD, astrocytes lose their polarization, detach from the BBB, become reactive and release inflammatory cytokines ( Liddelow et al, 2017 ; Sweeney et al, 2019b ; Cortes-Canteli and Iadecola, 2020 ). The crosstalk between astrocytes and microglia needs further understanding, although it has been extensively shown that they modulate each other’s activation state ( Joshi et al, 2019 ; McConnell et al, 2019 ; McAlpine et al, 2021 ). Astrocytes have also been reported to lose their expression of AQP4 early in AD ( Smith et al, 2019 ).…”

Section: The Neurovascular Unit: Function and Dysfunction In Stroke And Alzheimer’s Diseasementioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

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The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

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Section: The Neurovascular Unit: Function and Dysfunction In Stroke And Alzheimer’s Diseasementioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

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“…Moreover, inhibiting specific molecular pathways that mediate neuronal microglial communication is also a promising therapeutic approach, such as the application of probenecid in cerebral dysfunction of sepsis (Zhang et al, 2019 ). Novel research has reported that neuron-derived IL-33 (Nguyen et al, 2020 ) and astrocyte-derived IL-3 (McAlpine et al, 2021 ) as a key mediator of neuron-microglia crosstalk and astrocyte-microglia crosstalk, respectively, are associated with memory consolidation. It provides a new strategy for the future treatments of age-related memory decline (IL-33) and Alzheimer’s disease (IL-3).…”

Section: Discussionmentioning

confidence: 99%

Emerging Roles of Microglia in Neuro-vascular Unit: Implications of Microglia-Neurons Interactions

Ding

Guo

Luo

et al. 2021

Front. Cell. Neurosci.

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Microglia, which serve as the defensive interface of the nervous system, are activated in many neurological diseases. Their role as immune responding cells has been extensively studied in the past few years. Recent studies have demonstrated that neuronal feedback can be shaped by the molecular signals received and sent by microglia. Altered neuronal activity or synaptic plasticity leads to the release of various communication messages from neurons, which in turn exert effects on microglia. Research on microglia-neuron communication has thus expanded from focusing only on neurons to the neurovascular unit (NVU). This approach can be used to explore the potential mechanism of neurovascular coupling across sophisticated receptor systems and signaling cascades in health and disease. However, it remains unclear how microglia-neuron communication happens in the brain. Here, we discuss the functional contribution of microglia to synapses, neuroimmune communication, and neuronal activity. Moreover, the current state of knowledge of bidirectional control mechanisms regarding interactions between neurons and microglia are reviewed, with a focus on purinergic regulatory systems including ATP-P2RY12R signaling, ATP-adenosine-A1Rs/A2ARs, and the ATP-pannexin 1 hemichannel. This review aims to organize recent studies to highlight the multifunctional roles of microglia within the neural communication network in health and disease.

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“…Reactive astrocytes show disease-associated profiles and exert dynamic functions (neuroprotection and neurotoxicity) in AD [221][222][223][224][225]. Few studies have been reported on PET imaging of astrocytosis in AD animal models.…”

Section: Discussionmentioning

confidence: 99%

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

Ni¹

2021

Preprint

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Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research, and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models are essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models as well as in patients with Alzheimer’s disease, These tools have facilitated our understanding of disease mechanisms, and provided longitudinal monitoring of treatment effect in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood-brain barrier impairment and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes, and discuss outstanding challenges in disease animal models and future outlook in on-chip characterization of imaging biomarkers towards clinical translation.

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Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

Cited by 215 publications

References 39 publications

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Emerging Roles of Microglia in Neuro-vascular Unit: Implications of Microglia-Neurons Interactions

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

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